JAK1 pathway inhibitors for the treatment of chronic lung allograft dysfunction

Abstract

This disclosure relates to JAK1 pathway inhibitors and the use thereof in treating chronic lung allograft dysfunction such as, e.g., bronchiolitis obliterans syndrome.

What is claimed is: 
     
       1. A method of treating chronic lung allograft dysfunction in a subject, said method comprising administering to the subject 4 [3-(cyanomethyl)-3-(3′,5′-dimethyl-1H,1′H-4,4′-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide, or a pharmaceutically acceptable salt thereof. 
     
     
       2. The method of  claim 1 , wherein the chronic lung allograft dysfunction is bronchiolitis obliterans syndrome. 
     
     
       3. The method of  claim 1 , wherein the subject is a lung transplant recipient. 
     
     
       4. The method of  claim 1 , wherein the subject is a double lung transplant recipient. 
     
     
       5. The method of  claim 2 , wherein the subject suffers from Grade Op, Grade 1, Grade 2, or Grade 3 bronchiolitis obliterans syndrome as determined by International Society for Heart and Lung Transplantation (ISHLT) criteria. 
     
     
       6. The method of  claim 2 , wherein the treating of bronchiolitis obliterans syndrome comprises about a 10% or greater increase in FEVs at twelve weeks following the first administration of the 4-[3-(cyanomethyl)-3-(3′,5′-dimethyl-1H,1′H-4,4′-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro- 1-methylethyl]benzamide, or a pharmaceutically acceptable salt thereof. 
     
     
       7. A method of reducing the risk of bronchiolitis obliterans syndrome in a subject, said method comprising administering to the subject 4-[3-(cyanomethyl)-3-(3′,5′-dimethyl-1H,1′H-4,4′-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide, or a pharmaceutically acceptable salt thereof. 
     
     
       8. The method of  claim 7 , wherein the subject is a lung transplant recipient. 
     
     
       9. The method of  claim 7 , wherein the subject is a double lung transplant recipient. 
     
     
       10. A method of reducing the risk of lung re-transplantation in a subject, said method comprising administering to the subject 4-[3-(cyanomethyl)-3-(3′,5′-dimethyl-1H,1′H-4,4′-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide, or a pharmaceutically acceptable salt thereof. 
     
     
       11. A method of reducing the risk of hospitalization in a subject, said method comprising administering to said subject an effective amount of 4-[3-(cyanomethyl)-3-(3′,5′-dimethyl-1H,1′H-4,4′-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-R1S)-2,2,2-trifluoro-1-methylethyljbenzamide, or a pharmaceutically acceptable salt thereof, wherein said subject is (a) diagnosed with bronchiolitis obliterans syndrome; (b) has had a lung transplantation within 1 to 5 years prior to administering the, 4 [3-(cyanomethyl)-3-(3′,5′-dimethyl-1H,1′H-4,4′-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide, or a pharmaceutically acceptable salt thereof, and (c) does not have a decrease in FEVs attributable to a cause other than bronchiolitis obliterans syndrome. 
     
     
       12. A method of treating bronchiolitis obliterans syndrome in a subject, said method comprising administering to the subject a pharmaceutically acceptable salt of 4-[3-(cyanomethyl)-3-(3′,5′-dimethyl-1H,1′H-4,4′-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide. 
     
     
       13. The method of  claim 1 , wherein the pharmaceutically acceptable salt is 4-[3-(cyanomethyl)-3-(3′,5′-dimethyl-1H,1′H-4,4′-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(15)-2,2,2-trifluoro-1-methylethyl]benzamide phosphoric acid salt. 
     
     
       14. The method of  claim 7 , wherein the pharmaceutically acceptable salt is 4-[3-(cyanomethyl)-3-(3′,5′-dimethyl-1H,1′H-4,4′-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(15)-2,2,2-trifluoro-1-methylethyl]benzamide phosphoric acid salt. 
     
     
       15. The method of  claim 10 , wherein the pharmaceutically acceptable salt is 4-[3-(cyanomethyl)-3-(3′,5′-dimethyl-1H,1′H-4,4′-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(15)-2,2,2-trifluoro-1-methylethyl]benzamide phosphoric acid salt. 
     
     
       16. The method of  claim 11 , wherein the pharmaceutically acceptable salt is 4-[3-(cyanomethyl)-3-(3′,5′-dimethyl-1H,1′H-4,4′-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(15)-2,2,2-trifluoro-1-methylethyl]benzamide phosphoric acid salt. 
     
     
       17. The method of  claim 12 , wherein the pharmaceutically acceptable salt is 4-[3-(cyanomethyl)-3-(3′,5′-dimethyl-1H,1′H-4,4′-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(15)-2,2,2-trifluoro-1-methylethyl]benzamide phosphoric acid salt.